Autoimmune diseases are disorders in which the immune system produces autoantibodies directed against an endogenous antigen, with consequent injury to tissues. These self antigens, called also autoantigens, despite being normal tissue constituents, are the target of a humoral or cell-mediated immune response that characterizes the autoimmune disease.
Several connective tissue disorders including vascular diseases, such as vasculitis, systemic lupus erythematosus (SLE), and polymyositis, neurologic diseases such as multiple sclerosis and myasthenia gravis, and hematologic diseases such as idiopathic thrombocytopenia purpura (ITP) and anti-phospholipid syndrome (APS) seem to be caused by an autoimmune reaction. For some of these disorders, the self antigen has been identified and/or pathogenic autoantibodies have been identified and isolated.
No specific drugs exist nowadays for the treatment of autoimmune diseases and patients are treated with anti-inflammatory drugs such as corticosteroids and/or immunosuppressive drugs. All research being carried out in this field is directed to the development of drugs specific for each disease.
Anti-phospholipid antibodies have been associated with a variety of clinical phenomena, including arterial and venous thrombosis, thrombocytopenia, and obstetric complications. The term “anti-phospholipid syndrome” is used to link a variety of thrombotic events to antibodies against specific proteins involved in blood coagulation. Thrombotic events are reported in approximately 30% of patients with anti-phospholipid antibodies, with an overall incidence of 2.5% patients/year. Deep vein thrombosis of the legs and/or thrombotic events, and cerebral arterial thrombosis are the most common arterial complications. Obstetric complications include recurrent spontaneous miscarriages, fetal deaths, or fetal growth retardations. Women with anti-phospholipid antibodies are particularly prone to second or third trimester fetal death.
The anti-phospholipid syndrome (APS) is characterized by the presence of high titers of anti-cardiolipin and/or anti-β2GPI (beta-2-glycoprotein 1) antibodies which might have lupus anti-coagulant activity leading to thromboembolic phenomena, thrombocytopenia, recurrent fetal loss, as well as other multisystemic involvements. APS can emerge as a primary syndrome or as secondary syndrome to SLE (Hughes et al., 1986; McNeil et al., 1991).
Anti-β2GPI antibodies bind anionic phospholipids through the β2GPI molecule (McNeil et al., 1990; Igarashi et al., 1996). β2GPI is the target antigen for the autoimmune anti-β2GPI antibodies previously entitled ‘anti-cardiolipin/anti-phospholipid β2GPI dependent antibodies’. β2GPI (50 KD), initially described by Schultze et al. (1961), is composed of five respective consensus (‘sushi’ like) repeats (Kandiah and Krilis, 1994). β2GPI binds negatively charged phospholipids through a lysine-rich locus (Cys281–Cys288) located in the fifth domain (Hunt and Krilis, 1994) and possesses several in vitro properties which define it as an anticoagulant, i.e., it causes inhibition of prothrombinase activity, ADP-induced platelet aggregation, platelet factor IX production (Sheng et al., 1996). Employing site-directed mutagenesis of recombinant human β2GPI, a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity was identified (Sheng et al., 1996).
The anti-β2GPI antibodies have been considered to exert a direct pathogenic effect by interfering with hemostatic reactions occurring on the surface of platelets or vascular endothelial cells (Shi et al, 1993; Simantov et al., 1995). Passive transfer of these antibodies into naive mice or mice prone to develop APS, resulted in induction of experimental APS in mice (Blank et al., 1991). It has been shown recently (Del Papa et al., 1997; George et al., 1998) that human polyclonal and monoclonal anti-β2GPI antibodies react in vitro with endothelial cells through adherent β2GPI and induce differential endothelial cell activation. It is not clear to which epitopes on the β2GPI molecule these anti-β2GPI antibodies are directed, and the correlation to their biological activity.
Attempts have been made to find peptides that could mimic the self antigen-epitope and would inhibit the autoantibody/self antigen binding and consequent injury to the tissue. Thus, recently, peptides selected from phage-epitope libraries through binding to pathogenic monoclonal autoantibodies were shown to provide a surrogate antigen or mimotope that inhibits binding to the original antigen. Such peptides reflect the sequence or conformation of the antigen-binding site, and the fine specificity of the autoantibodies to the protein and non-protein, e.g. polysaccharides or dsDNA, antigens (Scott and Smith, 1990; Scott et al., 1992; Yayon et al., 1993).